While sub-Saharan Africa is home to 10% of the world's population, 90% of the world's HIV-infected children live in the region. The majority of these (16% or 280,000) live in South Africa, where HIV/AIDS accounts for 57% of deaths in children below 5 years of age. With improving access to antiretroviral treatment (ART), the disease is changing from fatal to chronic. However, central nervous system penetration by ART is limited and the brain is a reservoir for the virus, with dramatic consequences to the developing fetal/child brain. The Children with HIV early antiretroviral therapy (CHER) project is a project supported by the Comprehensive International Program for Research on AIDS in South Africa (CIPRA-SA), that has been following a cohort of children born with HIV. Controls were recruited by an interlinking vaccine trial also supported by CIPRA-SA. This is a unique and extremely well characterized cohort of children in three treatment arms in which (1) ART was delayed until immunological/clinical criteria were met, (2) ART commenced before 12 weeks and was interrupted after 40 weeks and (3) ART commenced before 12 weeks and was interrupted after 96 weeks. After two years, results showed that early HIV diagnosis and ART reduced early infant mortality by 76% and HIV progression by 75%. As an addendum to the CHER study, Dr. Barbara Laughton is performing comprehensive neurodevelopmental testing on the participants at the Cape Town Site. The children in the study will be turning 5 years old and returning for their last visit starting June 2010, and this is a unique opportunity to perform magnetic resonance neuroimaging in the children already enrolled to better understand the neural correlates of HIV/AIDS and effects of ART on the developing brain. Neurodevelopment studies in children with HIV in developing countries are rare and brain imaging studies of young children with HIV are rare anywhere. The Cape Town subset of the CHER cohort and controls (210 children) is being studied just a few minutes' walk from the Cape Universities Brain Imaging Center (CUBIC). This facility houses a state-of-the-art Siemens 3 T Allegra MRI research scanner optimized for brain imaging and is unique in Africa. We propose a comprehensive brain imaging study that includes morphometry, spectroscopy and diffusion tensor imaging. We aim to correlate cognitive and clinical metrics with quantitative imaging results, and hope to identify non-imaging metrics providing the best assessment of impaired brain development to guide intervention in resource-poor environments where imaging may be unavailable. This project represents a new collaboration between Dr. Barbara Laughton (Stellenbosch University), Dr. Ernesta Meintjes (University of Cape Town) and Dr. Andri van der Kouwe (Massachusetts General Hospital) and builds on an existing collaboration between the latter two investigators who are developing motion correction technology. The project will build capacity for advanced image acquisition and brain analysis methods in young children without the risk of sedation or anesthesia.